Perineurial cells in the human sural nerve possess tight junctions which in freeze-fracture replicas are seen to be composed of networks of branching and anastomosing P face strands and E face grooves. Isolated circular tight junctions (maculae occludentes) may represent attachment devices between adjacent perineurial lamellae. At the overlapping margins of the cells, a belt-like tight junction (zonula occludens) encircles the cells and is believed to comprise a paracellular diffusion barrier. As the permeability of the perineurium has been found to be altered in diabetic polyneuropathy, the zonulae occludentes have been studied. In freeze-fracture replicas from cases of diabetic polyneuropathy a mixed population of structurally normal and abnormal junctions was observed. In some, the strands were abnormally curved with reduced numbers of intersections, the intervening plasma membrane displaying prominent P face concavities and E face convexities. At other sites, the junctions were severely disorganized and represented by fragmented and isolated strands with few intersections and numerous free ends. These abnormalities resemble changes that have been produced experimentally in epithelial tight junctions by osmotic damage. The possibility is considered that similar mechanisms could result in the alterations of the perineurial tight junctions in diabetic polyneuropathy and account for its impaired permeability barrier properties.